Our research concerns the biosynthesis and functional characterization of peptide hormones of the pancreatic islet. Three hormones are being investigated. 1) We have recently identified pancreatic proglucagon as being an 18,000-dalton peptide in which the hormone sequence is located near, but not at, the COOH-terminus of the precursor form. We intend to perform related biosynthetic studies on other tissues (such as intestine) to identify controlling points in post-translational modifications which regulate the distribution of glucagon-related peptides in different tissues. 2) We will examine the biosynthesis of pancreatic polypeptide in pancreatic islets. It is our hope to identify the precursor of this peptide and to identify other small secreted peptides which arise from the conversion of the precursor form. 3) We will continue to examine defects in insulin biosynthesis which result from mutations in the insulin gene. These investigations identify potental causes of diabetes in man and provide important tools for studying the nature of proinsulin conversion (by identifying poorly converted forms) and the mechanism of insulin action (by identifying insulin variants with altered biological activity.